Study to Assess Impact of Dysport Injections Early After Stroke on Upper Limb Spasticity Progression (ONTIME Pilot)

Asian Multicentre, Double Blind, Randomised, Placebo Controlled Pilot Study, to Assess the Impact of Dysport® Intramuscular Injections When Administered Within the First 12 Weeks After Stroke on the Time to Spasticity Progression in Adult Subjects With Upper Limb (UL) Spasticity.

The purpose of this study is to investigate if early administration (i.e. within 12 weeks after stroke) of Dysport® 500 U injections may delay the appearance or the progression of upper limb symptomatic spasticity.

Study Overview

• Status: Completed
• Conditions: Stroke; Upper Limb Spasticity
• Intervention / Treatment: Biological: Botulinum toxin type A; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 42
• Phase: Phase 4

Contacts and Locations

Study Locations

• Malaysia
  • Kuala Lumpur, Malaysia, 59100
    • Neurology Laboratory -University Malaya Medical Centre
• Philippines
  • Manila, Philippines, 1003
    • Center for Neurodiagnostic and Therapeutic Services Metropolitan Medical Center
• Singapore
  • Singapore, Singapore, 569766
    • TTSH Rehabilitation Centre Ang Mo Kio Community Hospital
• Thailand
  • Bangkok, Thailand, 10700
    • Department of rehabilitation Medicine Faculty of medicine Siriraj Hospital, Madihol University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 2 to 12 weeks after first ever stroke according to the World Health Organisation criteria (previous transient ischaemic attack or clinically silent infarct on computerised tomography (CT)/magnetic resonance imaging (MRI) are not counted as previous stroke)
• Stroke confirmed by CT/MRI scan and classified as ischaemic/haemorrhagic stroke

• Presence of spasticity:

  • either symptomatic, based on symptomatic spasticity criteria (i.e. at least one of the following items: impacted passive/active function, involuntary movements, or pain ≥4 on a numeric pain rating scale [NPRS]), in addition to increased muscle tone [Modified Ashworth Scale, MAS ≥2])
  • or only increased muscle tone (MAS≥2)

Exclusion Criteria:

• Neuromuscular junction (NMJ) diseases, or any other neurological disorders (including prior local joint, tendon, and intrinsic muscle disorders) that could potentially interfere with assessment of spasticity in the primary targeted muscle group selected by the Investigator and in agreement with the subject
• Currently receiving drugs affecting NMJ transmission e.g. aminoglycosides, aminoquinolines, cyclosporine, D penicillamine
• Previous surgery of the affected muscles/ ligaments/tendons
• Severe comorbidities (e.g. congestive heart failure, myocardial infarction, multiple organ failure, hepatic renal failures, severe infections)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Treatment group; Dysport® 500U intramuscular injection	Biological: Botulinum toxin type A; Subjects to receive Dysport® 500U administered intramuscularly in the targeted upper limb.; Other Names: AbobotulinumtoxinA (Dysport®)
Placebo Comparator: Placebo Group; Placebo intramuscular injection	Drug: Placebo; Placebo administered intramuscularly in the targeted upper limb.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Time Between the Initial Injection and the Appearance of Reinjection Criteria as Evaluated by the Modified Ashworth Scale (MAS) and Spasticity Symptoms	The appearance of increased muscle tone was assessed using the MAS (scale ranges from 0 [no increase in muscle tone] to 4 [affected part rigid in flexion or extension]). For confirmation of reinjection criteria appearance, a subject had to have a MAS score in the primary targeted muscle group of ≥2 and at least 1 of the following 4 criteria confirming signs of symptomatic spasticity in the UL: A Numeric Pain Rating Scale (NPRS) pain score ≥ 4 (NPRS ranges from 0 [no pain] to 10 [severe pain]); An impact on passive function measured by a score of ≥ 1 on the 4-point Likert scale (scale ranges from 0 [no impact] to 3 [severe impact]); An impact on active function measured by a score of ≥ 1 on the 4-point Likert scale; An involuntary movements score ≥1 on the 4-point Likert scale in relevant upper limb. Results are reported overall for subjects with both symptomatic and asymptomatic spasticity.	From Week 4 up to Week 28

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Mean Change in MAS of the Primary Targeted Muscle Group.	Increased muscle tone in the primary muscle group (selected by the investigator at the first visit, based on his/her clinical judgement and in agreement with the subject, in one of the following muscle groups: elbow flexors or pronators, wrist flexors, or finger flexors) was assessed using the MAS. Scale ranges from 0 (no increase in muscle tone) to 4 (affected part rigid in flexion or extension). Least Squares (LS) mean change from baseline to each subsequent visit (including the subject's last study visit) of the MAS score is reported.	From baseline up to Week 28
Mean Change in Fugl-Meyer Assessment for Evaluation of UL Motor Impairment.	The Fugl-Meyer assessment is a validated tool for measuring motor functioning, balance, sensation, and joint functioning in the upper or lower limbs of subjects with post-stroke hemiplegia. The assessment scale is comprised of 155 items across 5 domains: motor functioning, sensory functioning, balance, joint range of motion and joint pain. For this study, only the UL motor part was assessed using the following criteria: A. Upper Extremity (from 0 to 36) B. Wrist (from 0 to 10) C. Hand (from 0 to 14) D. Coordination / Speed (from 0 to 6) Total motor function scores (A-D [from 0 to 66]) were calculated and LS mean changes from baseline up to (but not including) the visit when the reinjection criteria were met were reported. Higher values for change from baseline indicated a better outcome.	From baseline up to Week 28
Global Assessment of Changes at Last Visit	Global assessment of changes was assessed by the investigator from Week 4 up to (but not including) the visit when the reinjection criteria were met. This endpoint was assessed by the investigator using a 5-point Likert scale to answer the following question: How does your patient feel compared to his/her condition at the first visit?; Much better; Better; No change; Worse; Much worse Results are reported overall for subjects with both symptomatic and asymptomatic spasticity.	From Week 4 up to Week 28
Number of Concomitant Non-drug Therapy Sessions.	The number of non-drug therapy sessions that the subject received for UL spasticity in combination with injections of either Dysport® or placebo - up to and including the subject's last study visit - were recorded in the Electronic Case Report Form (eCRF) as part of concomitant medications and therapies evaluation at all study visits (Prior and Concomitant Non-Drug Therapies eCRF page). All concomitant therapies in the indication of "Post Stroke UL Spasticity" were counted by subject from first administration of Dysport® or placebo to last study visit. Concomitant non-drug therapies were defined as received any time during study (on or after the day of the first injection of Dysport® or placebo) regardless of the start or stop date. For each subject, overlapping sessions were defined as one therapy session using the earliest start date as the start date and the latest start date as the stop date.	From baseline up to Week 28
Mean Duration of Concomitant Non-drug Therapy Sessions.	The duration of non-drug therapy sessions that the subject received for UL spasticity in combination with injections of either Dysport® or placebo - up to and including the subject's last study visit - were recorded in the Electronic Case Report Form (eCRF) as part of concomitant medications and therapies evaluation at all study visits (Prior and Concomitant Non-Drug Therapies eCRF page). Overall duration of concomitant therapies in the indication of "Post Stroke UL Spasticity" was computed for the period from first administration of Dysport® or placebo to last study visit. Concomitant non-drug therapies were defined as received any time during study (on or after the day of the first injection of Dysport® or placebo) regardless of the start or stop date. For each subject, overlapping sessions were defined as one therapy session using the earliest start date as the start date and the latest start date as the stop date.	From baseline up to Week 28

Collaborators and Investigators

• Sponsor: Ipsen

Publications and helpful links

General Publications

• Rosales RL, Balcaitiene J, Berard H, Maisonobe P, Goh KJ, Kumthornthip W, Mazlan M, Latif LA, Delos Santos MMD, Chotiyarnwong C, Tanvijit P, Nuez O, Kong KH. Early AbobotulinumtoxinA (Dysport(R)) in Post-Stroke Adult Upper Limb Spasticity: ONTIME Pilot Study. Toxins (Basel). 2018 Jun 21;10(7):253. doi: 10.3390/toxins10070253.

Study record dates

Study Major Dates

• Study Start: December 1, 2014
• Primary Completion (Actual): March 1, 2016
• Study Completion (Actual): March 1, 2016

Study Registration Dates

• First Submitted: December 17, 2014
• First Submitted That Met QC Criteria: December 17, 2014
• First Posted (Estimate): December 22, 2014

Study Record Updates

• Last Update Posted (Actual): September 28, 2022
• Last Update Submitted That Met QC Criteria: September 15, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neurologic Manifestations; Musculoskeletal Diseases; Muscular Diseases; Neuromuscular Manifestations; Muscle Hypertonia; Stroke; Muscle Spasticity; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; Cholinergic Agents; Membrane Transport Modulators; Acetylcholine Release Inhibitors; Neuromuscular Agents; Botulinum Toxins; Botulinum Toxins, Type A; abobotulinumtoxinA
• Other Study ID Numbers: Y-79-52120-197

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes

IPD Plan Description

Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, annotated case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized, and study documents will be redacted to protect the privacy of study participants.

Any requests should be submitted to www.vivli.org for assessment by an independent scientific review board.

• IPD Sharing Time Frame: Where applicable, data from eligible studies are available 6 months after the studied medicine and indication have been approved in the US and EU or after the primary manuscript describing the results has been accepted for publication, whichever is later.
• IPD Sharing Access Criteria: Further details on Ipsen's sharing criteria, eligible studies and process for sharing are available here (https://vivli.org/members/ourmembers/).